Therapeutic composition and a method of coating implantable medical devices

ABSTRACT

A therapeutic composition is provided including a polysaccharide or a cationic peptide dissolved in an organic substance. The polysaccharide can be heparin or a derivative of heparin. The cationic peptide can be L-arginine, oligo-L-arginine or poly-L-arginine. The organic substance can be formamide. A method of coating an implantable medical device is also provided, comprising applying the therapeutic composition to the device and allowing the organic substance to evaporate. The device can be a stent.

CROSS REFERENCE

This application is a continuation of application Ser. No. 10/104,179,filed on Mar. 20, 2002 (which is incorporated herein by reference).

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compositions such as those used for coatingimplantable medical devices such as stents.

2. Description of Related Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the vessel wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis maydevelop shortly after the procedure and restenosis of the artery maydevelop over several months after the procedure, which may requireanother angioplasty procedure or a surgical by-pass operation. To reducethe partial or total occlusion of the artery by the collapse of arteriallining and to reduce the chance of the development of thrombosis andrestenosis, a stent is implanted in the lumen to maintain the vascularpatency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smalllumens via catheters, and then expanded to a larger diameter once theyare at the desired location. Biological therapy for reducing oreliminating thrombosis or restenosis can be achieved by medicating thestents. Medicated stents provide for the local administration of atherapeutic substance at the diseased site. In order to provide anefficacious concentration to the treated site, systemic administrationof such medication often produces adverse or toxic side effects for thepatient. Local delivery is a preferred method of treatment in thatsmaller total levels of medication are administered in comparison tosystemic dosages, but are concentrated at a specific site. Localdelivery thus produces fewer side effects and achieves more favorableresults.

Local delivery can be accomplished by coating the stent with a polymericcarrier containing a biologically active agent. A polymer dissolved inan organic solvent and the agent added thereto are applied to the stentand the organic solvent is allowed to evaporate, leaving a polymericcoating impregnated with the agent.

Biologically active agents including polysaccharides, e.g., heparin, andpolycationic peptides, e.g., poly-L-arginine have proven to providebeneficial effects in the treatment of thrombosis and restenosis, moreparticularly when used in conjunction with a stent. However,incorporation of these compounds into a polymeric carrier has proven tobe challenging due to such compounds' limited solubility. To pose theproblem more concretely by way of example, heparin is soluble in waterbut not in organic solvents, while conventional polymers used for thesustained release of heparin are soluble in organic solvents but notwater. To avoid the problem of solubility incompatibility, efforts havebeen made to fabricate heparin-polymer coatings from heparin-polymersuspensions. For example, U.S. Pat. Nos. 5,837,313 and 5,879,697,disclose micronizing heparin followed by physically blending with apolymer and solvent to form the suspension. The suspension methods havedrawbacks and disadvantages. The manufacturing process, for example,requires spraying equipment capable of handling particles. In addition,heparin-polymer suspensions lack sufficient stability in the absence ofsuspension agents and require constant agitation during the coatingprocess.

Alternatively, a complex of heparin with a cationic surfactant can beformed for converting the heparin into an organically soluble compound.Examples of suitable surfactant counter ions include benzalkonium andtridodecylmethyl ammonium. However, a surfactant-bound heparin has lowerantithrombotic activity because the surfactant alters heparin's chargebalance and binding coefficient with coagulation cofactors.

In view of the foregoing, there is a need to prepare a true solution ofpolysaccharides and cationic peptides with organic solvent compositionscommonly used to form polymeric coatings on implantable medical devices.

SUMMARY

In accordance with one embodiment of the invention, a therapeuticcomposition comprising a polysaccharide or a cationic peptide dissolvedin an organic substance is provided. The polysaccharide can be heparin,heparin salts, heparinoids, heparin-based compounds, heparin having ahydrophobic counter-ion, dermatan sulfate, keratan sulfate, chondroitinsulfate, hyaluronic acid and hyaluronates. The cationic peptide can beL-arginine, oligo-L-arginine, poly-L-arginine, or arginine-containingpeptide. The organic substance can be formamide.

In accordance with another embodiment of the invention, a method ofcoating an implantable medical device, for example a stent, is provided,comprising applying the above mentioned composition to the device andallowing the organic substance to evaporate.

In accordance with another embodiment, a method of coating a stent isprovided. The method includes the acts of preparing a solutioncomprising heparin or a heparin derivative in an organic substance;applying the solution to the stent; and allowing the organic substanceto evaporate. The organic substance can be formamide. In one embodiment,the method additionally includes combining the solution with acomposition including a polymer and optionally a biologically activesubstance. The polymer can be, for example, poly(ethylene-co-vinylalcohol), polyacrylates, poly (ethylene glycol), polyurethanes,polyesters, fluorinated polymers, and mixtures or combinations thereof.The biologically active substance can be, for example, actinomycin D,rapamycin, taxol, estradiol, poly(ethylene glycol)/poly(ethylene oxide),and derivatives thereof.

In accordance with another embodiment, a method for coating a stent isprovided, comprising preparing a solution comprising L-arginine, orpolymers or oligomers thereof, in an organic substance; applying thesolution to the stent, and allowing the organic substance to evaporate.The organic substance can be formamide. In one embodiment, the methodadditionally comprises combining the solution with a compositionincluding a polymer and optionally a biologically active substance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically depicts a cross-section of a coating on a stent inaccordance with one embodiment of the present invention.

FIG. 2 is a scanning electronic micrograph (SEM) showing a coated stent,where the stent coating included heparin applied in accordance with oneembodiment of the present invention.

DETAILED DESCRIPTION

FIG. 1 illustrates a partial cross section of a substrate 1 of animplantable medical device, such as a stent, having a coating. Thecoating can include, for example, an optional primer layer 2, areservoir layer 3, and an optional topcoat layer 4. According to oneembodiment of the present invention, the reservoir layer 3 can comprisea polymer and a polysaccharide. One example of a biologically activepolysaccharide is heparin or a heparin derivative. Heparin is known tohave an antithrombotic property, among other biologically activefunctions, and can be made from a mixture of sulfated polysaccharidechains based on D-glucosamine and D-glucoronic or L-iduronic acid.

“Heparin derivative” or “derivative of heparin” is intended to includeany functional or structural variation of heparin. Representativevariations include alkali metal or alkaline-earth metal salts ofheparin, such as sodium heparin (also known as hepsal or pularin),potassium heparin (formerly known as clarin), lithium heparin, calciumheparin (also known as calciparine), magnesium heparin (also known ascutheparine), and low molecular weight heparin (also known as ardeparinsodium). Other examples include heparan sulfate, heparinoids,heparin-based compounds and heparin having a hydrophobic counter-ion.

Examples of other polysaccharides include glycosaminoglycans (ormucopolysaccharides) such as keratan sulfate, chondroitin sulfate,dermatan sulfate (also known as β-heparin or as chondroitin sulfate B),hyaluronic acid and hyaluronates.

According to another aspect of the present invention, the reservoirlayer 3 can comprise highly positively charged peptides or proteins,such as L-arginine or oligomers and polymers of L-arginine. Theseoligomers and polymers are oligo- or polycationic peptides (or proteins)and are products of self-polycondensation of an amino acid L-arginine,also known as 2-amino-5-guanidinovaleric acid having a formulaNH═C(NH₂)—NH—CH₂—CH₂—CH(NH₂)COOH.

One example of oligomeric L-arginine that can be used is a heptamerknown as R7. Oligomers and polymers of L-arginine can be used in a formof a derivative, such as a salt, for example, hydrochloride,trifluoroacetate, acetate, or sulfate salts. Oligomers and polymers ofL-arginine, including R7, for the purposes of the present invention arecollectively designated as PArg. A general formula of PArg as ahydrochloride salt can be represented as H[—NH—CHR—CO—]_(m)OH.HCl, orPArg.HCl, where “m” can be an integer within a range of between 5 and1,000 and “R” is 1-guanidinopropyl radical having the structure—CH₂—CH₂—CH₂—NH—C(NH₂)═NH. In case of R7, m equals 7. “L-arginine,”“oligomers and polymers of L-arginine,” or “PArg” is intended to includepure L-arginine in its monomeric, oligomeric or polymeric form as wellas derivatives of L-arginine.

Formamide (H—CO—NH₂) can be used as a solubilizing agent for heparin,heparin derivatives, or PArg. Heparin or a heparin derivative or PArgcan be dissolved in formamide. At least 8% by mass of a solution ofheparin or a derivative thereof or PArg in formamide can be prepared.

A heparin-formamide solution or a PArg-formamide solution can be mixedwith a polymer. Should the polymer not be capable of dissolving informamide, the polymer can be first admixed with an organic solvent or amixture of organic solvents capable of dissolving the polymer. Thesolution can be applied onto the surface of the stent or onto the primerlayer 2 by spraying or dipping techniques as is well known to one ofordinary skilled in the art. Alternatively, the heparin-formamidesolution or the PArg-formamide solution can be applied followed byapplying the solution of the polymer in the organic solvent or themixture of organic solvents. The process can be repeated to obtain asuitable weight of the compound on the stent.

FIG. 2 is a SEM of a stent coating which includes heparin appliedaccording to one embodiment of the present invention. The coating shownon FIG. 2 was comprised of:

(a) a reservoir 3 having about 740 μg of total solids which includedpoly(ethylene-co-vinyl alcohol) (EVAL) and heparin in a 2:1 mass ratio;and

(b) a topcoat layer (about 54 μg of EVAL).

As evidenced by the micrograph, a very smooth coating was obtained.

The above-mentioned poly(ethylene-co-vinyl alcohol) (EVAL) is oneexample of a suitable polymer than can be employed to prepare thedrug-polymer layer 3, the optional primer layer 2 and/or the optionaltopcoat layer 4. EVAL has the general formula—[CH₂—CH₂]_(m)—[CH₂—H(OH)]_(n)—. EVAL is a product of hydrolysis ofethylene-vinyl acetate copolymers. EVAL can also be a terpolymerincluding up to, for example, 5 molar % of units derived from styrene,propylene and other suitable unsaturated monomers. Other suitablepolymers that can be used include poly(hydroxyvalerate), poly(L-lacticacid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lacticacid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane; poly(amino acids), cyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, such as poly(alkyl)(meth)acrylates, for example, poly(butyl methacrylate) and copolymers of butylmethacrylate, for instance, with hydroxymethyl methacrylate; vinylhalide polymers and copolymers (such as polyvinyl chloride), polyvinylethers (such as polyvinyl methyl ether), polyvinylidene halides (such aspolyvinylidene fluoride and polyvinylidene chloride), polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinylesters (such as polyvinyl acetate), copolymers of vinyl monomers witheach other and olefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon, rayon-triacetate, cellulose and itsderivatives, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, soluble fluorinated polymers and carboxymethyl cellulose.

The topcoat layer 4 may also contain a small amount of Na-heparin and/orPArg. The reservoir layer 3 can optionally include a therapeutic agentwith or without heparin or PArg. If such an agent is to be used, theagent can be either incorporated into the heparin or PArg composition,the polymer composition, or added subsequent to the combination of thesecompositions. Examples such of suitable therapeutic agents includeactinomycin D or derivatives and analogs thereof. Synonyms ofactinomycin D include dactinomycin, actinomycin IV, actinomycin I₁,actinomycin X₁, and actinomycin C₁. The active agent can also fall underthe genus of antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,anfiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. Taxol® byBristol-Myers Squibb Co. of Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S. A. of Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, of Peapack N.J.), and mitomycin(e.g. Mutamycin® from Bristol-Myers Squibb Co. of Stamford). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax® made by Biogen, Inc., of Cambridge, Mass.).Examples of such cytostatic or antiproliferative agents includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co. of Stamford),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc. of Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., of Whitehouse Station, N.J.),monoclonal antibodies (such as those specific for Platelet-DerivedGrowth Factor (PDGF) receptors), nitroprusside, phosphodiesteraseinhibitors, prostaglandin inhibitors, suramin, serotonin blockers,steroids, thioprotease inhibitors, triazolopyrimidine (a PDGFantagonist), and nitric oxide. An example of an antiallergic agent ispermirolast potassium. Other therapeutic substances or agents which maybe appropriate include alpha-interferon, genetically engineeredepithelial cells, rapamycin and its derivatives, estradiol and itsderivatives, poly(ethylene glycol)/poly(ethylene oxide) anddexamethasone.

The embodiments of the present invention are described with reference toa stent, such as a self-expandable or a balloon expandable stent. Othersuitable implantable medical device can also be similarly coated.Examples of such implantable devices include, but are not limited to,stent-grafts, grafts (e.g., aortic grafts), artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads(e.g., FINELINE and ENDOTAK, available from Guidant Corp.). Theunderlying structure of the device can be of virtually any design. Thedevice can be made of a metallic material or an alloy such as, but notlimited to, cobalt chromium alloy (ELGILOY), stainless steel (316L),“MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co. ofJenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

Embodiments of the present invention are further illustrated by thefollowing examples:

EXAMPLE 1

About 1 milliliter (1.133 gram) of formamide was added to 0.1 gram ofsodium heparin (NaHep) obtained from Aldrich Chemical Co. of Milwaukee,Wis. The suspension was heated at a temperature about 70° C. After about5 minutes of heating, sodium heparin was fully dissolved in formamide toform about 8.1 mass % NaHep solution. About 0.15 gram of EVAL wasdissolved in about 0.85 gram of dimethylacetamide (DMAC) to form 15%(mass) solution of EVAL. About 1 gram of the 15% EVAL solution wasfurther dissolved in a mixture of about 2 grams of DMAC and about 1 gramof methyl alcohol. This final EVAL solution was added to theNaHep-formamide solution prepared above. The two solutions werethoroughly mixed to form a clear heparin-polymer (NaHep-EVAL) solution.The NaHep-EVAL solution had a solid content of about 4.8 mass % and themass ratio of NaHep to EVAL of about 2:3.

At room temperature, the NaHep-EVAL solution was not sufficiently stableand developed substantial turbidity within about 15 minutes after themixing of the NaHep-formamide solution and the EVAL solution. In orderto avoid the phase separation, the NaHep-EVAL solution was heated atabout 70° C. for several minutes until the solution had become clearagain. When kept at a temperature of about 40° C, the NaHep-EVALsolution was clear and stable.

Prior to application, the NaHep-EVAL solution was filtered through 0.45micron filter. The NaHep-EVAL solution was then applied to a stent usinga spray apparatus, such as an EFD 780S spray nozzle with a VALVEMATE7040 control system, manufactured by EFD, Inc. of East Providence, R.I.The EFD 780S spray nozzle is an air-assisted external mixing atomizer.The composition was atomized by air and applied to the stent surfaces ata pressure of about 103.4 kPa (15 psi or 1.03 atm). The distance betweenthe spray nozzle and the stent surface was about 105 mm. The NaHep-EVALsolution was fed to the spray block at a pressure of about 23.3 kPa(3.35 psi or 0.23 atm).

The container with NaHep-EVAL solution was maintained at a temperatureof about 40° C., in order to avoid possible precipitation of the polymeror the drug. The spray block temperature was kept at about 60° C. Duringthe process of applying the composition, the stent can be optionallyrotated about its longitudinal axis, at a speed of 50 to about 150 rpm.The stent can also be linearly moved along the same axis during theapplication.

The NaHep-EVAL solution was applied to a 18-mm TETRA stent (availablefrom Guidant Corp.) in a series of 10-second passes, to deposit about 45μg of coating per spray pass. Between the spray passes, the stent wasdried for 10 seconds using flowing air with a temperature of about 80°C. to 100° C. A total of about 1.2 milligram of solid mass was applied.The coated stent was partially dried overnight at room temperature. Uponvisual inspection, no pool webs were observed.

EXAMPLE 2

About 1 milliliter (1.133 gram) of formamide was added to about 0.1 gramof poly-L-arginine sulfate. The suspension was heated at a temperatureof 50° C. After a few minutes of heating, PArg was fully dissolved informamide to form about 8.1 mass % PArg solution. About 0.15 gram ofEVAL was dissolved in about 0.85 gram of DMAC to form 15% (mass)solution of EVAL. About 1 gram of the 15% EVAL solution was furtherdissolved in a mixture of about 2 grams of DMAC and about 1 gram ofmethyl alcohol. This final EVAL solution was added to the PArg-formamidesolution. The two solutions were thoroughly mixed to form the PArg-EVALsolution. The PArg-EVAL solution had a solid content of about 4.8 mass %and the mass ratio of PArg to EVAL of about 2:3.

At room temperature, the PArg-EVAL solution was not sufficiently stableand developed substantial turbidity within about 15 minutes after themixing of the PArg-formamide solution with the EVAL solution. In orderto avoid phase separation, the PArg-EVAL solution was heated at about70° C. for several minutes until the solution became clear again. Whenkept at a temperature of about 40° C., the PArg-EVAL solution was clearand stable.

Using the process and equipment described in Example 1, the PArg-EVALsolution was applied to an 8-mm TETRA stent. 10 μg of coating per spraypass was applied. Between the spray passes, the stent was dried for 10seconds using flowing air with a temperature of about 80° C. to 100° C.A total of about 500 milligram of solid mass was applied. Upon visualinspection, no pool webs were observed.

EXAMPLE 3

A drug-polymer layer containing NaHep-EVAL was formed on a stentaccording to the procedure described in Example 1. A 2% (mass) solutionof EVAL in DMAC was prepared by mixing about 2 grams of EVAL and about98 grams of DMAC. Using the process and equipment described in Example1, the 2% EVAL solution was applied to an 8-mm TETRA stent coated withthe NaHep-EVAL drug-polymer layer to form a topcoat layer. About 10 μgof coating per spray pass was deposited. A total of about 33 μg of solidmass was applied as a topcoat layer followed by drying in a convectionoven at about 70° C. for about 2 hours.

Using the process and equipment described in Example 1, the 2% EVALsolution was also applied to an 18-mm TETRA stent coated with theNaHep-EVAL drug-polymer. layer to form a topcoat layer. About 20 μg ofcoating per spray pass was deposited. A total of about 120 μg of solidmass was applied as a topcoat layer followed by drying in a convectionoven at about 70° C. for about 2 hours.

EXAMPLE 4

A drug-polymer layer containing PArg-EVAL was formed on a stentaccording to the procedure described in Example 1. A 2% (mass) solutionof EVAL in DMAC was prepared by mixing about 2 grams of EVAL and about98 grams of DMAC. Using the process and equipment described in Example1, the 2% EVAL solution was applied on an 8-mm TETRA stent coated withthe PArg-EVAL drug-polymer layer to form a topcoat layer. About 10 μg ofcoating per spray pass was deposited. A total of about 40 μg of solidmass was applied as a topcoat layer followed by drying in a convectionoven at about 70° C. for about 2 hours.

Using the process and equipment described in Example 1, the 2% EVALsolution was also applied to an 18-mm TETRA stent coated with thePArg-EVAL drug-polymer layer to form a topcoat layer. About 20 μg ofcoating per spray pass was deposited. A total of about 400 μg of solidmass was applied as a topcoat followed by drying in a convection oven atabout 70° C. for about 2 hours.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A therapeutic composition comprising heparin dissolved in an organicsolvent.
 2. The therapeutic composition of claim 1, wherein dissolved isdefined as at least 8% by mass of heparin solubility in the organicsolvent.
 3. The therapeutic composition of claim 1, wherein the organicsolvent comprises formamide.
 4. The therapeutic composition of claim 1,additionally including one or a combination of a polymer, a therapeuticsubstance and a second solvent.
 5. The therapeutic composition of claim4, wherein the therapeutic substance is paclitaxel, decetaxel,rapamycin, or derivatives thereof.
 6. A method of coating an implantablemedical device, comprising applying the composition of claim 1 to thedevice and removing the organic solvent.
 7. The method of claim 6,wherein the device is a stent.
 8. The method of claim 6, wherein thecomposition additionally comprises one or a combination a polymer, atherapeutic substance and a solvent.
 9. The method of claim 8, whereinthe device is a stent.
 10. The method of claim 8, wherein thetherapeutic substance is paclitaxel, decetaxel, rapamycin, orderivatives thereof.
 11. The method of claim 10, wherein the device is astent.